Selpercatinib Elicits Encouraging Antitumor Activity in Pediatric RET-Altered Solid Tumors

Among 8 patients with measurable disease, the objective response rate (ORR) was 50% (95% CI, 16%-84%). Four patients had partial responses (PRs), 2 patients had stable disease (SD), 1 patient had progressive disease (PD), and 1 patient was not evaluable, translating to a clinical benefit rate of 75% (95% CI, 35% -97%).

“These data provide further evidence that selpercatinib is effective in pediatric patients with RET mutant medullary thyroid carcinoma [MTC] and RET fusion-positive thyroid cancer. These patients should be universally screened for RET changes,” lead study author Daniel A. Morgenstern, MBBChir, PhD, director of the New Agent and Innovative Therapy Program and Therapeutic MIBG Program, co-director of the Neuroblastoma Program in Hematology/Oncology at SickKids, and medical director of the Oncology and BMT/CT Clinical Trials Support Unit, said in a virtual presentation of the data.

RET fusions are the most common useful change in children with papillary thyroid cancer (PTC), and the majority of children with MTC have germline RET mutations associated with MEN2 syndrome.

Selpercatinib is a highly selective and potent RET inhibitor with central nervous system (CNS) activity that is approved for the treatment of adult patients with metastatic RET fusion positive non-small cell lung cancer, adult and pediatric patients 12 years of age and older with advanced or metastatic RET mutant MTC requiring systemic therapy, and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer requiring systemic therapy and being radioiodine insensitive.2

Its favorable efficacy and safety profile in adult patients formed the basis for its evaluation in a pediatric population.

To that end, investigators conducted a multicenter, phase 1/2 study of selpercatinib in pediatric patients, ages 6 months to 21 years at least, with advanced RET-altered solid or CNS tumors. Patients in the European Union and Canada had to be at least 12 years old to be eligible to enroll.

In the Phase 1 dose-escalation/confirmation portion of the study, patients received a starting dose of 92 mg/m2 selpercatinib twice daily, which is equivalent to the recommended adult dose of 160 mg twice daily.

The phase 2 expansion portion of the study consisted of 4 cohorts, in which patients with RET fusion-positive solid tumors with measurable disease (cohort 1), RET mutant MTC with measurable disease (cohort 2), RET fusion-positive CNS- tumors with measurable disease (cohort 3), and patients not eligible for cohorts 1 to 3 with a RET change (cohort 4).

The maximum tolerated dose/recommended Phase 2 dose (RP2D) and ORR served as the primary endpoints of the Phase 1 and Phase 2 portions of the study, respectively. The RP2D was confirmed separately for patients younger than 2 and 2 years and older.

As of the data cut-off on March 30, 2021, 12 patients were enrolled. The patients had a median age of 14 years (range 2-20). Six male and 6 female patients were enrolled each. The majority of patients (n = 9) had metastatic disease at study entry, prior treatment – ​​surgery (n = 9), radiotherapy (n = 4) and systemic therapy (n = 3) – and a performance of Karnofsky/ Lansky status of 100 (n = 7). Three patients with locally advanced disease were also included.

The majority of patients were diagnosed with MTC (n = 8), followed by PTC (n = 2), rhabdomyosarcoma (n = 1), and osteosarcoma (n = 1). Both cases of sarcoma had a variant of unknown significance in RET.

The response data indicated that the 1 patient with osteosarcoma had PD, but all other patients with thyroid cancer and RET abnormalities had SD or PR.

“RET changes in pediatric cancers outside of MTC and thyroid cancer are rare, and as expected, no responses were observed for RET variants of unknown significance,” Morgenstern said.

Additional results showed that median progression-free survival was not achieved at a median follow-up of 8 months from the first dose of selpercatinib. The median duration of response was not reached at a median follow-up of 5 months from first response, and all 4 PRs are ongoing.

“The important message is that of the patients being studied, the vast majority — 9 out of 12 — remain in therapy,” Morgenstern said.

Notably, all 8 patients with MTC experienced a biochemical response through a reduction in calcitonin and variable reductions in carcinoembryonic antigen, regardless of their radiologic response.

In terms of safety, no dose-limiting toxicities were reported with the starting dose of selpercatinib, which became the RP2D. In the extension cohorts, 1 patient discontinued treatment due to PD, 1 due to patient non-compliance, and 1 due to treatment-independent adverse events (AEs).

“Overall, this drug was very well tolerated with minimal toxicity, consistent with adult experience. The most common side effects were diarrhea, hyperphosphatemia, nausea and abnormal liver enzymes,” Morganstern said.

An analysis showed similar results with the pharmacokinetics of selpercatinib exposure at day 8 of the first 3 patients enrolled in the study versus those of the LIBRETTO-001 study (n = 222) and a pediatric compassionate use program (n = 4).

“While the data for the pediatric population is rather sparse, the important message here is that overall exposures in the pediatric population are broadly similar to those in adults, supporting the use of this dose in the extension cohorts,” Morgenstern concluded.


Morgenstern D, Mascarenhas L, Campbell M, et al. Oral selpercatinib in pediatric patients with advanced RET-altered solid or primary CNS tumors: preliminary results from the phase 1/2 LIBRETTO-121 study. J Clin Oncol. 2021;39(suppl 15):10009. doi:10.1200/JCO.2021.39.15_suppl.10009Retevmo prescribing information. FDA. Revised May 2020. Accessed June 6, 2021.

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